title: Elimination of macrophages drives LXR-induced regression both in initial and advanced stages of atherosclerotic lesion development.
abstract: While numerous studies have aimed to develop strategies to inhibit the development and progression of atherosclerosis, recent attention has focussed on the regression of pre-existing atherosclerotic plaques. As important regulator of total body cholesterol homeostasis, the liver X receptor (LXR) could possibly be an important target to induce regression. Here, we describe the effect of LXR activation by the synthetic agonist T0901317 on lesion regression in different mouse models with early fatty streak lesions or advanced collagen-rich lesions. Although T0901317 caused a dramatic increase in plasma (V)LDL levels in low-density lipoprotein (LDL) receptor knockout mice, no further increase in lesion size was observed, which points to beneficial LXR activity in the vascular wall. In normolipidemic C57BL/6 mice with cholate diet-induced atherosclerotic lesions, T0901317 treatment improved plasma lipoprotein levels and induced lesion regression (-43%, p<0.05). Apolipoprotein E (APOE) reconstitution in APOE knockout mice by means of bone marrow transplantation dramatically improved plasma lipoprotein profiles and resulted in a marked regression of initial (-45%, p<0.001) and advanced lesions (-23%, p<0.01). Atherosclerosis regression was associated with a decrease in the absolute macrophage content (-84%, p<0.001). T0901317 supplementation further decreased the size of early (-71%, p<0.001 vs baseline; -48%, p<0.01 vs chow diet alone) and more advanced atherosclerotic lesions (-36%, p<0.001 and -17%, p=0.06 respectively). In conclusion, our study highlights the potential of LXR agonist T0901317 to stimulate removal of macrophages from atherosclerotic lesions ultimately leading to a highly significant plaque regression of both early and advanced atherosclerotic lesions.
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, P.O. Box 9502, 2300RA Leiden, The Netherlands; Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Heidelberglaan 100, 3584CX Utrecht, The Netherlands. Electronic address: stoepmvander@lacdr.leidenuniv.nl.
authors.forename: Marco
authors.initials: M
authors.lastname: van der Stoep
authors.forename: Zhaosha
authors.initials: Z
authors.lastname: Li
authors.forename: Laura
authors.initials: L
authors.lastname: Calpe-Berdiel
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: van der Sluis
authors.forename: Peshtiwan
authors.initials: P
authors.lastname: Saleh
authors.forename: Heather J
authors.initials: HJ
authors.lastname: McKinnon
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Smit
authors.forename: Suzanne J A
authors.initials: SJ
authors.lastname: Korporaal
authors.forename: Theo J C
authors.initials: TJ
authors.lastname: Van Berkel
authors.forename: Miranda
authors.initials: M
authors.lastname: Van Eck
authors.forename: Menno
authors.initials: M
authors.lastname: Hoekstra
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D016026:Bone Marrow Transplantation; D002452:Cell Count; D015243:Cholesterol, VLDL / Q000097:blood; D004032:Diet; D004195:Disease Models, Animal; D005260:Female; D006845:Hydrocarbons, Fluorinated / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors / Q000819:agonists*; D058226:Plaque, Atherosclerotic / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D011973:Receptors, LDL / Q000235:genetics; D012720:Severity of Illness Index; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D014280:Triglycerides / Q000097:blood; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D001057:Apolipoproteins E; D015243:Cholesterol, VLDL; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011973:Receptors, LDL; D013449:Sulfonamides; D014280:Triglycerides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
keywords: Atherosclerosis; Bone marrow transplantation; Liver X receptor; Regression; T0901317